The objective of the present proposal is to examine te mechanism whereby two water retaining pharmacologic agents (chlorpropamide and carbamazepine) and two agents that cause a water losing disorder (lithium and demeclocycline) exert their effect on water excretion. The experiments are tailored to focus in each case on the to date undefined mechanisms whether central (vasopressin release, thirst) or renal (vasopressin dependent and independent). Methods to be employed include metabolic balance studies, measurements of vasopressin release, use of vasopressin free diabetes insipidus rats, measurements of systemic and renal hemodynamics, determination of inner medullary tonicity and inner medullary blood flow. These in vivo measurements are complemented by biochemical studies performed in dissected vasopressin sensitive segments of the nephron, the medullary ascending limb, the cortical, outer and inner medullary collecting ducts. Both in situ cAMP content as well as the activities of adenylate cyclase and cAMP phosphodiesterase are performed with microassays with the view of defining the effects on the whole system. Both tissues of animals treated with the drugs and acute medium manipulations of the agents in tissues of untreated rats will be undertaken. The roles of prostaglandins and calcium will also be explored. The studies will provide correlates of in vivo water excretion with in vitro biochemical perturbations in the primary effector of vasopressin action - the cAMP system.